The immune system provides the primary mechanism of defense against disease in living organisms, whereby pathogens and foreign organisms are detected and eliminated by components of the immune system. The innate immune response functions as the first line of defense against infection, comprising diverse cellular components including granulocytes (basophils, eosinophils and neutrophils), mast cells, natural killer cells (NKC) and antigen presenting cells (APCs), such as macrophages and dendritic cells (DC) and soluble factors, such as complement proteins. The adaptive immune response as the second line defense is slower to develop, and includes the selection of cellular versus humoral responses for the elimination of pathogens. Cellular immunity is primarily Th1-induced, leading to the differentiation of cytotoxic T-cells, natural killer cells (NKC) and activated macrophages that serve to destroy compromised host cells (e.g. virus or pathogen infected cells). Humoral immunity manifests as increased antigenic specificity and antigen memory, whereby Th2 activation and cytokine production leads to the generation of B cells producing antibodies and memory cells that facilitate the recognition of pathogen-derived antigens and pathogen elimination.
The innate immunity in the newborn mammal is underdeveloped, such that disease resistance in the newborn depends heavily on the passive acquisition of maternal antibodies received through maternal breast milk, in particular colostrum. In parallel, development of the infant immune system is induced by immune-stimulating components present in the maternal milk. Development of the immune system in newborn mammals fed formula milk rather than maternal milk is delayed due to a deficiency of the major immunity-inducing and -conferring components that would otherwise be provided in maternal milk.
Maintenance of the immune system remains essential for health throughout life, and thus immune-compromised individuals of any age, as well as elderly individuals with a steadily declining immunity, represent patient groups at greater risk of disease-related mortality.
Vaccination to raise immune resistance to infectious diseases is the most effective method of improving public health. The range of diseases for which vaccines are available is increasing continually, and the use of these vaccines to protect the adult population, in particular the growing elderly population is increasing. Vaccination, either prophylactic or therapeutic, stimulates the body's immune system to recognize an antigenic agent resembling a given disease-causing agent; to destroy it; and “remember” it, so that the immune system can more easily recognize and destroy the disease-causing agent upon reexposure. Typically such an agent is made from weakened or killed forms of the pathogenic microbe, its toxins or one of its surface proteins.
Since the efficacy of vaccination depends on the ability of the vaccinated subject to raise an effective immune response, the benefits of vaccination are reduced in individuals in which the immune system is either not fully developed, as in new-born or young infants, or individuals in whom the immune system is either reduced, compromised or in decline, as in some adults and the elderly. Accordingly, there exists a need for agents that can enhance the immune responsiveness in these patient groups, in particular their immune response to vaccination. Public health programs to vaccinate these large patient populations must be extremely safe and, hence, both the agents used to enhance the immune response to vaccination and the means used for their administration must meet these safety requirements.
Osteopontin (OPN) is an extracellular matrix protein expressed by a number of cell types including osteoclasts, osteoblasts, macrophages, activated T-cells, smooth muscle cells and epithelial cells. It is present in several tissues including bone, kidney, placenta, smooth muscle and secretory epithelia. OPN is able to mediate cell adhesion and migration, and is associated with normal tissue remodeling processes such as bone resorption, angiogenesis, wound-healing and tissue injury. OPN is also expressed in certain diseased states e.g. restenosis, atherosclerosis, renal diseases and tumorigenesis. Modified transcription of the gene encoding OPN has been observed, wherein alternative splice transcripts lead to expression of different forms of OPN in certain disease states (Bissonnette et al 2012). OPN exerts many of its biological effects by interacting with integrins, which comprise a large family of heterodimeric transmembrane receptors that mediate both cell-cell and cell-matrix interactions, and may play a role in inflammatory diseases.
WO 98/56405 A1 relates to a method of modulating (augmenting or reducing) an individual's immune response by altering (increasing or decreasing) osteopontin activity; but lacks evidence to support a therapeutic effect of administering OPN (e.g. recombinant OPN) to a subject.
WO 00/63241 A2 relates to Eta-1/osteopontin as a regulator of immune responses; but fails to evidence that administration of OPN enhances immune resistance to infectious disease.
Khajoee V et al., 2006 CLINICAL AND EXPERIMENTAL IMMUNOLOGY, 143(2):260-268; relates to the role of osteopontin in defense against mycobacterial infection; based on studies conducted with human monocyte-derived macrophage cell cultures.